Glutamic acid (GLU) is thought to serve as the primary excitatory neurotransmitter in the brain. The broad representation of GLU is cortical and limbic pathways, its role in neurodegenerative processes, and the cognitive and psychotomimetic effects of interfering with GLU neurotransmission implicate GLU as an important neurotransmitter for understanding the pathobiology of psychiatric disorders. We have characterized a dipeptide -- N-acetyl-aspartyl-glutamate (NAAG) -- which is localized to putative GLU pathways and is released upon electrical stimulation. NAAG may antagonize NMDA receptors, but is also catabolized to free GLU by a specific peptidase, NAALADase. We hypothesize that NAAG may serve a dual function as l) a precursor for synaptic GLU and ,2) an antagonist at certain NMDA receptors. Accordingly, NAALADase may act as a "fulcrum," determining the balance between NAAG inhibition and GLU liberated excitation. Reciprocal alterations in NAAG/NAALADase levels have been demonstrated in seizure models, neurodegenerative disorders, and schizophrenia. To better understand the relationships between NAAG and GLU neurotransmission, we propose a detailed molecular characterization of NAALADase to determine its localization and regulation of expression. We will further define abnormalities of NAAG and NAALADase levels in neuropsychiatric disorders, including schizophrenia, Huntington's Disease and Alzheimer's Disease. And, we will attempt to characterize the enzyme which synthesizes NAAG which could, among other opportunities, permit immunostaining of NAAG synthesizing neurons in formaldehyde fixed tissue. Together, these studies clarify the potential involvement of NAAG and GLU in major mental disorders.